Lecture 7 (EXAM 2)

Question 1

A patient was presented with a yellow-colored sclera, and elevated levels of enzymes, what might the patient suffer from?

Answer 1

-Jaundice, damaged liver is not able to metabolize Bilirubin (high level of Bilirubin in the blood)

-disruption of liver cells causing exposure of liver enzymes to the blood

Question 2

What do increased prothrombin, reduced plasma bicarbonate, and reduced glomerular filtration, and elevated serum creatinine indicate?

Answer 2

increased prothrombin: enzymes for blood clotting are reduced due to impaired liver

reduced glomerular filtration and elevated serum creatinine: kidney is affected too

Question 3

What is the predominant organ that performs Biotransformation?

Answer 3

The liver (f.e. first pass)
Notice: other organs also perform Biotransformation

Question 4

How are molecules altered during Biotransformation

Answer 4

Primarily by making it more water soluble to increase renal excretion

Question 5

What are the two types of Biotransformations?

Answer 5

Phase 1: simple Oxidations

Phase 2: synthetic reactions or conjugation reaction
-> Addition of a large water-soluble molecule

Question 6

What are the water-soluble groups that are added in Phase 2 reactions?

Answer 6

-Glucuronic acid
-GSH-Gluthanionie (3 amino acids)
-Sulfate (SO4-2)
-Methyl
-Acetyl

Question 7

What does the general scheme of biotransformation look like?

Answer 7

-A drug undergoes Phase 1 and gets oxidized (-OH)
-the drug undergoes Phase 2, whereby a water-soluble drug is conjugated to the drug by linking to the oxygen

-Phase 2 reactions can also occur before Phase 1

Question 8

What does the general scheme of biotransformation look like?

Answer 8

Absorption –> Metabolism –> Elimination
from Lipophilic to Hydrophilic

-A drug undergoes Phase 1 and is oxidized (-OH)
-the drug undergoes Phase 2, whereby a water-soluble drug is conjugated to the drug by linking to the oxygen

-Phase 2 reactions can also occur before Phase 1, several sequences and combinations are possible

Question 9

What are the outcomes of Phase 1 Biotransformation?

Answer 9

-drug gets metabolized causing increased (prodrug) or decreased activity
OR
-inactive drug metabolite

-either way, the drug will be more water-soluble

Question 10

Other sequences of Biotransformation?

Answer 10

-Drug undergoes Phase 1 modification and gets eliminated without undergoing Phase 2

-Drug gets eliminated without undergoing Phase 1 and Phase 2 Biotransformation (f.e. Metformin)

Question 11

What are primary and secondary metabolites?

Answer 11

-After undergoing Biotransformation (f.e. Phase 1) there are fractions of metabolites -> 1 primary metabolite with the highest amount and multiple secondary metabolites
-the metabolites may have increased, or decreased activity, be TOXIC, or are deactivated

-after Phase 1 metabolism the metabolites have different fates (they can undergo Phase 1 again, Phase 2, or elimination with different efficacy changes)

if there are so many different outcomes, how can we predict the outcome of certain drugs?? f.e. how do we know that drug XY will undergo first pass,

Question 12

What is the meaning of Cytochrome P450?

Answer 12

Cyto = inside the cell
chrome = color
P450 = absorbs light at lambda 450

Question 13

What is required for CYP450 to absorb light at Lambda 450?

Answer 13

Carbon monoxide (CO)

Question 14

How many genes code for CYP 450?

Answer 14

approximately 50 genes

Question 15

What are the CYP450-dependent oxidation reactions?

Answer 15

-Aromatic hydroxylations (there is a toxic Epoxide metabolite)
-Aliphatic hydroxylations
-Epoxidation

-Oxidative dealkylation (carbon with oxygen comes off)
-N-Oxidation (nitrogen gets oxidized)
-S-Oxidation
-Deamination followed by an oxidation
-Desulfuration followed by an oxidation
-Dechlorination (toxic free radical intermediate)

Question 16

What are the Cytochrome P450-independent oxidation reactions?

Answer 16

-Flavin monooxygenase (Ziegler’s enzyme)
-Amine oxidases
-Dehydrogenations

-Reductions
-Hydrolyses

Question 17

Nomenclature of CYP450 2C 19

Answer 17

2C = Family
19 = gene location (chromosome)

Question 18

What do CYPs contain in the middle of their structure?

Answer 18

-Porphyrin ring

-often contain a metal ion (Fe-ion) in the middle of the ring that is important for enzymatic activity

Question 19

What is the enzyme that provides electrons for CYP450 to work?

Answer 19

P450 reductase providing e- for CYP450

-both work together in a cycle to metabolize drugs

Question 20

What is the state of Fe in the porphyrin ring in the first step of the cycle?

Answer 20

Oxidized state: Fe3+ (ferric)

Question 21

What happens to Fe in the second step?

Answer 21

Reduction to Fe2+ (ferrous) by the electron provided from P450 reductase

Question 22

Where does the P450 reductase get its electron from?

Answer 22

-from NADPH which reduces a portion of the P450 reductase

-the P450 reductase will carry over the e- to the Fe3+ in CYP450

Question 23

Step 3 of the CYP450 cycle

Answer 23

-P450 reductase donates another e-

-CYP450 carries two e- -> the 2nd electron attracts molecular O2
-O2 binds to the enzyme complex = CYP450 with Fe2+ and the bound drug
–> unstable complex

Question 24

What happens to the unstable CYP45-drug complex?

Answer 24

-The drug will accept one oxygen
RH (drug) –> ROH

-the other oxygen will attract available H atoms and will form H2O

-the oxidized drug (ROH) is not metabolized and loses affinity to the complex and dissociates

Question 25

What property does a substrate need to bind to CYP450?
(broad substrate specificity)

Answer 25

CYP450 makes substrates more water-soluble -> so the substrate need to lack water solubility
–>the LIPOPHILICITY of a substrate determines how likely it is going to bind to CYP450